U.S. patent number 10,648,969 [Application Number 15/124,171] was granted by the patent office on 2020-05-12 for method and device for quality controlling a blood-based product.
This patent grant is currently assigned to CellTool GmbH. The grantee listed for this patent is CellTool GmbH. Invention is credited to Karin Schutze, Raimund Schutze.
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United States Patent |
10,648,969 |
Schutze , et al. |
May 12, 2020 |
Method and device for quality controlling a blood-based product
Abstract
A method and device for quality controlling a blood-based
product. In order to control the quality of a blood-based product
which comprises an erythrocyte concentrate, a thrombocyte
concentrate, a granulocyte concentrate, a leukocyte concentrate,
whole blood and/or blood plasma, a Raman spectrum is recorded. By
means of evaluating the Raman spectrum, it is determined whether
the blood-based product can be used for a transfusion.
Inventors: |
Schutze; Raimund (Tutzing,
DE), Schutze; Karin (Tutzing, DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
CellTool GmbH |
Bernried |
N/A |
DE |
|
|
Assignee: |
CellTool GmbH (Bernried,
DE)
|
Family
ID: |
52633271 |
Appl.
No.: |
15/124,171 |
Filed: |
March 6, 2015 |
PCT
Filed: |
March 06, 2015 |
PCT No.: |
PCT/EP2015/054724 |
371(c)(1),(2),(4) Date: |
September 07, 2016 |
PCT
Pub. No.: |
WO2015/132384 |
PCT
Pub. Date: |
September 11, 2015 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20170219568 A1 |
Aug 3, 2017 |
|
Foreign Application Priority Data
|
|
|
|
|
Mar 7, 2014 [DE] |
|
|
10 2014 003 386 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N
33/5091 (20130101); G01N 33/49 (20130101); G01N
33/5094 (20130101); G01N 33/80 (20130101); G01N
21/65 (20130101); G01N 33/15 (20130101); G01N
2201/12 (20130101); G01N 2333/195 (20130101) |
Current International
Class: |
G01N
33/50 (20060101); G01N 21/65 (20060101); G01N
33/80 (20060101); G01N 33/15 (20060101); G01N
33/49 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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|
1242937 |
|
Feb 2006 |
|
CN |
|
WO-2006130921 |
|
Dec 2006 |
|
WO |
|
2008027942 |
|
Mar 2008 |
|
WO |
|
2010048678 |
|
May 2010 |
|
WO |
|
2014007759 |
|
Jan 2014 |
|
WO |
|
Other References
Saade et al. Spectroscopy (2008) 22: 387-395 (Year: 2008). cited by
examiner .
Hobro et al. Analyst (Mar. 7, 2013) 138: 3927-3933 (Year: 2013).
cited by examiner .
Dasgupta et al. J. Biomed. Optics (2011) 16(7): 07709, pp. 1-9
(Year: 2011). cited by examiner .
Nam et al. Tropical Med. International Health (2010) 15(12):
1436-1441 (Year: 2010). cited by examiner .
Karin Schutze et al., "Laser World of Photonics--DGLM Application
Panel Unmet Needs in Photonics and Medicine: Novel cell analysis
based on Raman spectroscopy." Photon Lasers Med, Jan. 1, 2013, vol.
2, pp. 361-369. cited by applicant .
S. Koch et al., "Novel cell identification: markerfree and suitable
for living cells." Proceedings of SPIE, Jun. 18, 2013 SPIE--ISSN
0277-786X, Jun. 18, 2013, vol. 8798, p. 87980J. cited by applicant
.
Jurgen Luhm et al., "Potential use of Raman Spectroscopy in the
Quality Control of blood products." http://celltool.de/files/201311
luhm-drk_raman_red.pdf, published on the web Nov. 1, 2013. cited by
applicant.
|
Primary Examiner: Lankford; Blaine
Attorney, Agent or Firm: Sand, Sebolt & Wernow Co.,
LPA
Claims
The invention claimed is:
1. A method for quality controlling a blood-based product, wherein
the method comprises: providing a computer comprising one or a
plurality of processors or controllers; storing, in a database in a
memory of the computer, a plurality of reference spectra, wherein
the stored plurality of reference spectra includes one or more of:
a position of Raman peaks and/or wavenumber ranges of fresh cells
of different cell types of blood based products, wherein the
blood-based products comprise one or more of an erythrocyte
concentrate, a thrombocyte concentrate, a granulocyte concentrate,
a leukocyte concentrate, whole blood and blood plasma; a position
of Raman peaks and/or wavenumber ranges of functionally modified
cells of the different cell types of the blood based products and
information regarding ranges of multi-dimensional spaces of a
cluster analysis, in which the reference spectra are respectively
arranged; collecting, in an optical trap, at least one cell of a
sample of a liquid blood-based product from one of the plurality of
blood donors recording a Raman spectrum of the at least one cell of
the sample by means of Raman spectroscopy; comparing the recorded
Raman spectrum of the at least one cell of the sample with the
plurality of reference spectra stored in the database; evaluating
one or more of cell age, cell death, sterility, levels of impurity
and cell functionality of the at least one cell of the sample based
on results of the comparison; and determining whether the liquid
blood-based product donated by the one of the plurality of blood
donors is usable for a transfusion based on results of the
evaluation.
2. The method according to claim 1, wherein the evaluating includes
identifying a functional modification of the at least one cell of
the sample.
3. The method according to claim 2, wherein the evaluating further
comprises quantitatively determining which proportion of the at
least one cell of the sample is subject to a functional
modification.
4. The method according to claim 3, wherein the quantitatively
determining of which proportion of the at least one cell of the
sample is subject to the functional modification further comprises
respectively subjecting a plurality of recorded Raman spectra to a
principal component analysis.
5. The method according to claim 1, wherein the evaluating further
comprises identifying the presence of bacteria or other impurities
in the sample of the blood-based product.
6. The method according to claim 1, wherein the evaluation
comprises a spectral analysis of the Raman spectrum.
7. The method according to claim 1, wherein the optical trap is
produced by an excitation beam of a Raman spectroscopy system.
8. The method according to claim 1, comprising wherein the at least
one cell of the sample of the liquid blood-based product is
selected from a group consisting of erythrocytes, thrombocytes,
granulocytes and leukocytes.
9. The method according to claim 1, further comprising: declaring
the blood-based that has been tested by subjecting the sample to
Raman spectroscopy usable; and transfusing a patient with the
blood-based product.
10. The method according to claim 1, wherein: the collecting of the
at least one cell of the sample of the liquid blood-based product
includes collecting a plurality of cell types; and the evaluating
includes identifying a functional modification of different
categories of cells of the plurality of cell types.
11. The method according to claim 10, further comprising: recording
several internal functional modifications of the different
categories of cells.
Description
FIELD OF THE INVENTION
The invention relates to methods and devices for quality
controlling a blood-based product. The invention in particular
relates to such methods and devices by means of which it can be
determined whether an erythrocyte concentrate, a thrombocyte
concentrate, a granulocyte concentrate, a leukocyte concentrate, a
reserve with whole blood and/or a reserve with blood plasma may
still be used for transfusion.
BACKGROUND OF THE INVENTION
Blood-based products such as for example erythrocyte concentrates,
thrombocyte concentrates, granulocyte concentrates, leukocyte
concentrates, whole blood reserves or blood plasma reserves, are
today used to a large extent in hospitals in the form of blood
reserves. The obtainment of concentrates from human blood donors
for transfusion is a complex process. Under ideal storage
conditions at a temperature of between 2.degree. C. and 6.degree.
C., the storage life of the reserves with erythrocyte concentrate
is for example 42 days. Typically up to now, thrombocyte reserves
have had to be discarded after a shorter time period.
The quality controlling of blood-based products is often carried
out by corresponding confirmations from specialist personnel that a
cold chain has been maintained. Since an interruption of the cold
chain cannot be excluded in many cases, which can significantly
reduce the duration of the storage life, reserves for which it
cannot be safely determined whether the cold chain has been
maintained uninterrupted are likely also discarded for safety
reasons even before the expiration date is reached. It may also be
the case that the blood donors carry germs or negative factors
which were not visible or measurable at the time of the blood
donation.
An objective quality control is desired. According to the
corresponding guidelines, at least 210.sup.11 thrombocytes and less
than 1 million leukocytes or 3 million residual erythrocytes should
be contained for example in a thrombocyte concentrate. The pH value
of a thrombocyte concentrate should be between 6.4 and 7.8. The
product must be sterile until the end of the maximum storage
life.
Compliance with these guidelines can be quantitatively verified. To
this end, counts of the thrombocytes, erythrocytes and leukocytes
can for example be carried out in processes using microscopes.
Conventional methods for the quantitative quality controlling of
blood-based products, in which for example the thrombocyte count,
the erythrocyte count, the protein content, the pH value and/or the
calcium content is determined, are time-consuming and expensive, in
particular because these samples may no longer be used for
transfusion. According to the hemotherapy directive of the German
Medical Association (as of 2010), 1% of all blood-based products,
but at least 4 bags must be withheld for quality controlling. A
proportion of 0.4 n of the products must be verified when verifying
the sterility and is thus also not suitable for use.
Furthermore, conventional methods provide no information or only
very limited information regarding the functionality of the cells
contained in the blood-based product. The functionality state or
the storage life duration of the blood-based products could also be
connected to the condition or state of the donor. Donor-specific
possibilities for quality testing are not known at present.
SUMMARY OF THE INVENTION
The object of the invention is to indicate methods and devices
which enable an objective verification of blood. In particular, the
object underlying the exemplary embodiments is to indicate methods
and devices which enable an objective verification of blood-based
products. Blood-based products are here in particular understood as
bags with an erythrocyte concentrate, bags with thrombocyte
concentrate, bags with granulocyte concentrate, bags with leukocyte
concentrate, whole blood reserves or blood plasma reserves.
Methods and devices are indicated herein. The method is provided
for quality controlling a blood-based product, which comprises an
erythrocyte concentrate, a thrombocyte concentrate, a granulocyte
concentrate, a leukocyte concentrate, whole blood or blood plasma,
wherein the method comprises: recording a Raman spectrum by means
of Raman spectroscopy of a sample of the blood-based product, and
determining whether the blood-based product can be used for a
transfusion by means of evaluating the Raman spectrum. By means of
evaluating the Raman spectrum, a functional modification of cells
of at least one cell type of the blood-based product is identified
in order to determine whether the blood-based product can be used
or a transfusion, wherein the cell type is selected from a group
consisting of erythrocytes, thrombocytes, granulocytes and
leukocytes. By means of evaluating the Raman spectrum, it is
quantitatively determined which proportion of the cells of at least
one cell type is subject to a functional modification. In order to
quantitatively determine which proportion of the cells of at least
one cell type is subject to the functional modification, a
plurality of recorded Raman spectra are respectively subjected to a
principal component analysis. By means of evaluating the Raman
spectrum, the presence of bacteria or other impurities in the
blood-based product is identified in order to determine whether the
blood-based product can be used for a transfusion. The evaluation
of the Raman spectrum comprises a spectral analysis of the Raman
spectrum. The recording of the Raman spectrum comprises collecting
at least one cell of the sample in an optical trap in order to
record the Raman spectrum. The optical trap is produced by means of
an excitation beam of a Raman spectroscopy system. In the
aforementioned methods, the at least one cell is selected from a
group consisting of erythrocytes, thrombocytes, granulocytes and
leukocytes. In accordance with an aspect of the disclosed method,
there is also disclosed a device for quality controlling a
blood-based product which comprises an erythrocyte concentrate, a
thrombocyte concentrate, a granulocyte concentrate, a leukocyte
concentrate, whole blood and/or blood plasma, wherein the device
comprises a Raman spectroscopy system in order to record a Raman
spectrum of a sample of the blood-based product), and an evaluation
device which is coupled to the Raman spectroscopy system and which
is configured to determine by means of the recorded Raman spectrum
whether the blood-based product can be used for a transfusion. The
evaluation device for performing a cluster analysis, in particular
a principal component analysis, is configured to identify
functional modification of cells of at least one cell type of the
blood-based product, wherein the cell type is selected from a group
consisting of erythrocytes, thrombocytes, granulocytes and
leukocytes. The evaluation device is configured to quantitatively
determine by means of the cluster analysis which proportion of the
cells of the at least one cell type is subject to a functional
modification and is used to perform the method disclosed above. In
accordance of another aspect of the invention, the disclosed device
is used to identify a contamination, a disease or a progression of
disease, and wherein the device comprises a Raman spectroscopy
system in order to record at least one Raman spectrum of at least
one blood sample, and an evaluation device which is coupled to the
Raman spectroscopy system and which is configured to automatically
identify a disease or a progression of disease by means of the
recorded at least one Raman spectrum. The disease that may be
identified by the disclosed device is selected from a group
consisting of tumour diseases, blood coagulation disorders and
thrombosis.
In the case of a method for quality controlling a blood-based
product, which comprises an erythrocyte concentrate, a thrombocyte
concentrate, a granulocyte concentrate, a leukocyte concentrate,
whole blood and/or blood plasma, a Raman spectrum is recorded by
means of Raman spectroscopy of a sample of the blood-based product.
By means of evaluating the Raman spectrum, it is determined whether
the blood-based product can be used for a transfusion.
When recording the Raman spectrum of a sample, the fluid itself can
be measured (for example the calcium content and/or protein
content). The cellular components such as erythrocytes, leukocytes,
granulocytes or thrombocytes can, however, also be identified and
examined with regard to their functionality. These cellular
components can be collected individually or in a group with a few
cells in an optical trap and measured by recording the Raman
spectrum. The Raman spectrum can also be recorded for a sample
which is a microdroplet or the Raman spectrum can be recorded for a
sample which is the dried residue of a droplet after evaporation.
The sample can also be a pellet which is produced by means of
centrifugation and for which the Raman spectrum is recoded.
The use of Raman spectroscopy enables not only verification of
whether the relevant cell types are present, but also a
determination of the biological functionality. In particular, it
can be determined whether and, optionally, which proportion of
erythrocytes, leukocytes, granulocytes or thrombocytes is subject
to a molecular modification. An example of such a molecular
modification is cell death (apoptosis or necrosis). Modifications
of the composition or the quantity ratios and concentration of the
biomolecules in the cells can also be identified by means of
evaluating the Raman spectrum, said modifications restrict
functionality of the cell. As a result, conclusions can be drawn
regarding the usability and functionality of the blood-based
product.
The use of Raman spectroscopy also enables a determination of
whether germs or bacteria are present in the reserve. Infected
cells, e.g. infected erythrocytes may also be identified, for
example in the case of malaria. Furthermore, the types of
impurities of the reserve can also be determined from the Raman
spectrum and/or the number of impurities can be estimated.
The evaluation can take place automatically by means of an
evaluation device. The evaluation device may be a computer. The
evaluation device may comprise one or a plurality of processors or
controllers. The evaluation device can generate an optical and/or
acoustic output as a result of the evaluation which shows whether
the blood-based product can still be used for a transfusion. The
evaluation device can output information regarding the state of
cellular components of the blood-based product and/or information
regarding impurities contained in the blood-based product as a
result of the evaluation.
In the case of evaluating the Raman spectrum, a spectral analysis
of the Raman spectrum can be carried out.
By evaluating the Raman spectrum, an erythrocyte decay or a
thrombocyte decay, an erythrocyte cell death or a thrombocyte cell
death or another functional modification of a cellular component of
the blood-based product can be identified. By evaluating the Raman
spectrum, a restriction of the functionality of erythrocytes,
thrombocytes, granulocytes or leukocytes can be identified.
In order to identify which proportion of cells of a cell type, e.g.
which proportion of erythrocytes, thrombocytes, granulocytes or
leukocytes is subject to a functional modification, which makes the
blood-based product unsuitable for a transfusion, a cluster
analysis of a plurality of Raman spectra of cells of this cell type
can automatically be performed. The cluster analysis can be a
principal component analysis. By means of the cluster analysis, it
can be quantitatively identified whether cells have to be assigned
to a cluster of intact cells or to another cluster of functionally
impaired cells. The number of cells in the different clusters
provides information regarding which proportion of cells of the
cell type is subject to the functional modification.
For blood-based products, which comprise a plurality of different
cellular components of the blood, a cluster analysis can
distinguish not only between intact cells and functionally modified
cells, but also between different cell types.
An assignment to different cell types can take place for a cluster
analysis or for a different analysis of the recorded Raman spectra
for example by means of different wavenumber ranges. In order to
identify thrombocytes and/or in order to identify functional
modifications of thrombocytes, at least one wavenumber in the
wavenumber range of 1296 cm.sup.-1 to 1333 cm.sup.-1 can for
example be evaluated in order to determine whether the blood-based
product can be used for a transfusion.
In order to identify erythrocytes and/or in order to identify
functional modifications of erythrocytes, at least one wavenumber
from one or a plurality of wavenumber ranges of 1650 to 1600
cm.sup.-1, from 1350 to 1250 cm.sup.-1, from 1180 cm.sup.-1 to 1120
cm.sup.-1, from 1100 cm.sup.-1 to 1050 cm.sup.-1, from 930
cm.sup.-1 to 890 cm.sup.-1 or from 700 cm.sup.-1 to 650 cm.sup.-1
can for example be evaluated in order to determine whether the
blood-based product can be used for a transfusion.
In order to perform the cluster analysis, the mentioned wavenumber
ranges do not necessarily have to be evaluated, but rather other
principal components can also be evaluated.
In the case of evaluating the Raman spectrum, one or a plurality of
Raman peaks can be identified and can optionally be further
evaluated, which are assigned to red blood cells. The Raman
spectrum can be evaluated in the case of at least one and
optionally in the case of a plurality of wavenumbers which are
selected from the group consisting of 669 cm.sup.-1, 750 cm.sup.-1,
752 cm.sup.-1, 999 cm.sup.-1, 1122 cm.sup.-1, 1210 cm.sup.-1, 1444
cm.sup.-1, 1543 cm.sup.-1 and 1617 cm.sup.-1.
In the case of evaluating the Raman spectrum, a Raman peak can for
example be identified, which is assigned to guanine. A spectral
weight or a width of the Raman peak, which is assigned to guanine,
can be determined.
Alternatively or additionally, in the case of evaluating the Raman
spectrum, a Raman peak can for example be identified, which is
assigned to deoxyribonucleic acid. A spectral weight or a width of
the Raman peak, which is assigned to deoxyribonucleic acid, can be
determined The Raman peak may be an amide-III-band or a
a-Helix.
Alternatively or additionally, in the case of evaluating the Raman
spectrum, a Raman peak can for example be identified, which is
assigned an erythrocyte decay, an erythrocyte cell death or to a
different functional impairment of erythrocytes. A spectral weight
or a width of the Raman peak, which is assigned to an erythrocyte
cell death, can be determined.
Alternatively or additionally, in the case evaluating the Raman
spectrum, a Raman peak can for example be identified, which is
assigned a thrombocyte decay, to a thrombocyte cell death or to a
different functional impairment of thrombocytes. A spectral weight
or a width of the Raman peak, which is assigned to a thrombocyte
cell death, can be determined.
In order to identify one or a plurality of the mentioned Raman
peaks, the Raman spectrum can be evaluated in a predefined
wavenumber range. For example, the Raman spectrum can be evaluated
in a wavenumber range of 1296 cm.sup.-1 to 1333 cm.sup.-1 in order
to determine whether the blood-based product can be used for a
transfusion.
The Raman spectrum can undergo a spectral analysis. For example, an
analysis of mean value spectra, a principal component analysis
and/or a support vector machine (SVM) can be used in order to
determine whether the blood-based product can be used for a
transfusion.
In order to record the Raman spectrum, at least one cell of the
sample can be collected in an optical trap. In this manner, cells,
which are in solution, can also be recorded in a spectroscopic
manner. In the case of further cells, for example cells which are
on an objective slide base, it is not absolutely necessary to
collect the cells in an optical trap.
A non-focussed beam can be used for measuring a Raman spectrum if
the sample has the form of a dried droplet or pellet, but also in
order to determine a broad spectrum directly in an amount of fluid.
To this end, light conductor-based Raman spectroscopy systems or a
Raman spectroscopy system, which is not optimally focused through
an objective, can for example be used since such systems usually
measure in a planar manner, wherein the covered dimensions can
reach up into the millimeter range.
In order to record the Raman spectrum, at least one optical light
conductor, for example an optical fibre, can be used in order to
direct the excitation beam and/or the scattered light.
The optical trap can be produced by an excitation beam of Raman
spectroscopy. In this manner, a Raman signal can be maintained with
a good signal-noise ratio using simple means.
The excitation beam can have a wavelength of between 700 and 1064
nm.
The at least one cell can be selected from a group consisting of
erythrocytes, thrombocytes and leukocytes. The at least one cell
can be a granulocyte.
A functionality of erythrocytes and/or thrombocytes can be
evaluated by Raman spectroscopy. Additionally or alternatively, it
can be quantitatively recorded by Raman spectroscopy whether and,
where appropriate what quantity of impurities are contained in the
blood-based product.
In order to identify bacteria and germs, a quantity of blood-based
product can for example be removed from the reserve and further
processed. The quantity of blood-based product can be further
processed in order to concentrate any impurities present. In order
to concentrate the impurities, the cellular proportions such as
erythrocytes and/or thrombocytes and/or leukocytes can for example
be separated at least in part before the sample is further
concentrated, for example by a combination with hydrogel. The
sample can be examined by Raman spectroscopy in order to verify the
sterility and thus the usability of the blood-based product.
The sample can be removed from the blood-based product in order to
perform the Raman spectroscopy. The blood-based product can
comprise a plastic bag, in which an erythrocyte concentrate, a
thrombocyte concentrate, a granulocyte concentrate, a leukocyte
concentrate or whole blood can be contained. The sample can be
removed from the blood-based product by hand using a syringe or
automatically by a robot.
The Raman spectroscopy can be performed while the blood-based
product is contained in the bag. The reserve is still available as
a sterile reserve after the quality controlling. The blood-based
product can be contained in a bag which is designed for use in a
Raman spectroscopy system. The bag can consist of a material which
has high transmissivity for the excitation beam and the Raman
scattered light of the relevant biological objects (for example
erythrocytes, thrombocytes, bacteria and/or germs). The bag can
comprise a window made of a material which has high transmissivity
for the excitation beam and the Raman scattered light of the
relevant biological objects (for example erythrocytes,
thrombocytes, leukocytes, bacteria and/or germs).
A device for quality controlling a blood-based product, which
contains an erythrocyte concentrate, a thrombocyte concentrate, a
granulocyte concentrate, a leukocyte concentrate, whole blood
and/or blood plasma, comprises a Raman spectroscopy system for
recording a Raman spectrum of a sample of the blood-based product.
The device comprises an evaluation device which is coupled to the
Raman spectrometer and which is configured to determine by means of
the recorded Raman spectrum whether the blood-based product can be
used for a transfusion.
The evaluation device can be a computer. The evaluation device can
comprise one or a plurality of processors or controllers. The
evaluation device can produce an optical and/or acoustic output as
a result of the evaluation which shows whether the blood-based
product can be used for a transfusion.
The evaluation device can be coupled to an image sensor of the
Raman spectroscopy system. The image sensor can be a CCD sensor or
a CMOS sensor.
In order to identify which proportion of cells of a cell type, e.g.
which proportion of erythrocytes, thrombocytes, granulocytes or
leukocytes is subject to a functional modification, which makes the
blood-based product unsuitable for a transfusion, the evaluation
device can be configured to perform a cluster analysis of a
plurality of Raman spectra of cells of this cell type. The cluster
analysis can be a principal component analysis. The evaluation
device can be configured to quantitatively identify by means of the
cluster analysis whether cells have to be assigned to a cluster of
intact cells or to another cluster of functionally impaired cells.
The number of cells in the different clusters can be determined by
the evaluation device in order to determine which proportion of
cells of the cell type is subject to the functional
modification.
For blood-based products, which comprise a plurality of different
cellular components of the blood, the evaluation device, by means
of a cluster analysis, can distinguish not only between intact
cells and functionally modified cells, but also between different
cell types.
An assignment to different cell types by means of the evaluation
device can take place in the case of a cluster analysis or in the
case of a different analysis of the recorded Raman spectra for
example by means of different wavenumber ranges. In order to
identify thrombocytes and/or in order to identify functional
modifications of thrombocytes, at least one wavenumber in the
wavenumber range of 1296 cm.sup.-1 to 1333 cm.sup.-1 can for
example be evaluated by means of the evaluation device in order to
determine whether the blood-based product can be used for a
transfusion.
In order to identify erythrocytes and/or in order to identify
functional modifications of erythrocytes, at least one wavenumber
from one or a plurality of wavenumber ranges of 1650 to 1600
cm.sup.-1, from 1350 to 1250 cm.sup.-1, from 1180 cm.sup.-1 to 1120
cm.sup.-1, from 1100 cm.sup.-1 to 1050 cm.sup.-1, from 930
cm.sup.-1 to 890 cm.sup.-1 or from 700 cm.sup.-1 to 650 cm.sup.-1
can for example be evaluated in order to determine whether the
blood-based product can be used for a transfusion.
In order to perform the cluster analysis by means of the evaluation
device, the mentioned wavenumber ranges do not necessarily have to
be evaluated, but rather other principal components can also be
evaluated.
The evaluation device can be configured to identify a Raman peak
which is assigned to a thrombocyte cell death in order to determine
whether the reserve can be used for a transfusion. The evaluation
device can be configured to identify a Raman peak which represents
a modification of the composition of the biomolecules in the cell
which restricts the functionality of the cell.
The evaluation device can be configured to identify and further
evaluate a Raman peak which is assigned to the red blood cells.
The evaluation device can be configured to carry out a spectral
analysis of the Raman spectrum.
The Raman spectroscopy system can comprise a laser for producing an
excitation beam for the Raman spectroscopy. The laser can produce
light with a wavelength of between 700 nm and 1064 nm.
The Raman spectroscopy system can comprise optical components in
order to produce an optical trap by means of the excitation beam in
which at least one cell of the sample can be collected in order to
record the Raman spectrum. The optical components can comprise a
lens. The optical components can comprise a light conductor in
which the excitation beam for the Raman spectroscopy is directed.
By means of collection in an optical trap, in particular cells,
which are movable, can also be subjected to the Raman spectroscopy.
In the case of a Raman spectroscopy on dried droplets or pellets,
the production of an optical trap is not necessarily required.
The device can be configured to automatically perform the method
according to an exemplary embodiment.
According to further exemplary embodiments, the devices and methods
can be used in order to automatically identify diseases and
progressions of disease.
A device according to a further exemplary embodiment is configured
to identify a disease or a progression of disease and comprises a
Raman spectroscopy system for recording at least one Raman spectrum
of at least one blood sample and an evaluation device which is
coupled to the Raman spectroscopy system and which is configured to
evaluate the Raman spectrum in order to identify a disease or a
progression of disease.
The device can be configured to identify disease or a progression
of a disease by means of evaluating the Raman spectrum which is
selected from a group consisting of tumour diseases, blood
coagulation disorders and thrombosis.
The device can be configured to identify and evaluate Raman peaks,
which are assigned to erythrocytes, in one or a plurality of Raman
spectra in order to identify the disease or the progression of
disease.
The evaluation device can be configured to objectively and
quantitatively examine the blood-based product by means of
evaluating one or a plurality of Raman spectra. A comparison with
reference spectra stored in a database can be carried out in order
to determine which cell types are present and/or in order to
quantify the number of cells of one or a plurality of cell types
and/or in order to identify functional modifications of cells of
one or a plurality of cell types. Alternatively or additionally,
processing of the Raman spectra can be carried out, for example by
means of a cluster analysis in order to identify different cell
types. A comparison with reference spectra stored in a database can
be carried out in order to identify bacteria, germs or other
impurities.
The evaluation device can be configured to store recorded Raman
spectra of the blood-based product in a non-volatile manner in a
memory.
The evaluation device can comprise a memory in which information
regarding the position of Raman peaks of different cell types of a
blood-based product are stored. Information regarding the position
of Raman peaks of erythrocytes can be stored in the memory.
Alternatively or additionally, information regarding the position
of Raman peaks of thrombocytes can be stored in the memory.
Alternatively or additionally, information regarding the position
of Raman peaks of granulocytes can be stored in the memory.
Alternatively or additionally, information regarding the position
of Raman peaks of leukocytes can be stored in the memory. The
information regarding the position of the Raman peaks can be stored
in a different manner. For example, the relevant wavenumber ranges
for fresh cells and for functionally modified cells can be stored.
Information regarding ranges of multi-dimensional spaces of a
cluster analysis, in which the spectra are respectively arranged,
can be stored.
A method for identifying a contamination, a disease or a
progression of disease according to a further exemplary embodiment
comprises recording at least one Raman spectrum of at least one
blood sample and an evaluation device which is coupled to the Raman
spectroscopy system and which is configured to evaluate the Raman
spectrum in order to identify a disease or a progression of
disease.
The method can be performed automatically using the device
according to an exemplary embodiment.
The obtainment of the blood sample is not part of the claimed
method.
BRIEF DESCRIPTION OF THE FIGURES
The invention is explained further by means of preferred exemplary
embodiments below with reference to the drawing.
FIG. 1 shows a schematic illustration of a device according to an
exemplary embodiment.
FIG. 2 is a flow diagram of a method according to an exemplary
embodiment.
FIG. 3 shows a schematic illustration of a Raman spectrum which is
evaluated by devices and methods according to exemplary
embodiments.
FIG. 4 shows a schematic illustration of a Raman spectrum which is
evaluated by devices and methods according to exemplary
embodiments.
FIG. 5 shows a schematic illustration of a static evaluation of the
Raman spectrum of a sample.
FIG. 6 shows a schematic illustration of a static evaluation of the
Raman spectrum of a further sample.
FIG. 7 shows a schematic illustration of a static evaluation of the
Raman spectrum of a sample.
FIG. 8 shows a schematic illustration of a static evaluation of the
Raman spectrum of a further sample.
FIG. 9 shows a schematic illustration of Raman spectra which are
evaluated by devices and methods according to exemplary
embodiments.
FIG. 10 shows a schematic illustration of the Raman spectroscopy in
combination with an optical trap.
FIG. 11 shows a schematic illustration of a reserve which is
configured for performing the method on the closed reserve.
DESCRIPTION OF EXEMPLARY EMBODIMENTS
The features of the different described embodiments can be combined
with each other, insofar as this is not expressly excluded in the
description below.
Devices and methods according to exemplary embodiments can be used
for quality controlling blood-based products. The term "blood-based
product" here includes reserves with erythrocyte concentrate,
reserves with thrombocyte concentrate, reserves with granulocyte
concentrate, reserves with leukocyte concentrate, reserves with
whole blood and reserves with blood plasma. Granulocyte
concentrates also contain other leukocytes in addition to
granulocytes which can cause a GvHD (graft versus host) reaction in
the recipient. The reproductive capability of the lymphocytes is
irreversibly impaired by means of irradiation. A leukocyte
concentrate is obtained by means of leukopheresis from donor blood
and in particular contains granulocytes. The leukocyte concentrate
is maintainable only for a few hours and is administered for
infection prophylaxis in the case of pronounced, but reversible
leukocyte deficiency.
In the case of devices and methods according to exemplary
embodiments, a Raman spectrum of a sample of the blood-based
product is recorded. The Raman spectrum is evaluated in order to
determine whether the blood-based product is still suitable for a
transfusion. The blood-based product can be a blood reserve,
wherein for example an erythrocyte concentrate, a thrombocyte
concentrate, a granulocyte concentrate, a leukocyte concentrate,
whole blood or blood plasma is contained in a suitable
container.
FIG. 1 is a schematic illustration of a device 1 according to an
exemplary embodiment. The device 1 is configured to determine
whether a blood reserve 2 is suitable for a transfusion. The
corresponding determination takes place by means of a Raman
spectrum which the device 1 records and can automatically evaluate.
A sample of a blood-based product 3, which may for example be an
erythrocyte concentrate, a thrombocyte concentrate, a granulocyte
concentrate, a leukocyte concentrate, whole blood or blood plasma,
is used for a Raman spectroscopy in order to determine whether the
blood-based product 3 may be used for a transfusion. The
manufacture of the blood reserve 2, which can be carried out
according to conventional techniques, is not subject matter of the
methods and devices disclosed here.
The device 1 comprises a Raman spectroscopy system 10 and an
evaluation device 20. The Raman spectroscopy system 10 is
configured to record a Raman spectrum of a sample 9 of the
blood-based product 3. A quantity of the blood-based product 3 can
be removed from the blood reserve 2 and after further processing
can be prepared as a sample 9 for the Raman spectroscopy system 10.
The sample 9 can contain blood cells which are movable in a
solution. The sample 9 can contain dried blood or a pellet which is
produced from the blood-based product 3.
In the case of further designs, the Raman spectroscopy system 10
can also be designed such that the Raman spectrum is recorded
directly on the blood reserve 2 without a quantity of the
blood-based product 3 having to be first removed from said blood
reserve. An entire blood reserve can then be inserted into the
Raman spectroscopy system.
The Raman spectroscopy system 10 comprises a light source 11 which
can in particular be a laser. The light source 11 is configured to
output an excitation beam 17. The excitation beam 17 can for
example have a wavelength in the range between 700 nm and 1064 nm,
e.g. approximately 785 nm. A Raman spectrometer 14 receives light
18 scattered on the sample 9 by Stokes processes and/or Anti-Stokes
processes. The Raman spectrometer 14 can comprise a diffractive
element 15 and an image sensor 16 in order to record the Raman
spectrum of the sample 9. The Raman spectroscopy system 10 can
comprise further elements in a manner known per se, for example
focussing optical elements 12, 13, which can be designed as lenses,
and/or diaphragms.
Then device 1 comprises an evaluation device 20. The evaluation
device 20 can be a computer or can comprise a computer. The
evaluation device 20 is coupled to the Raman spectroscopy system
10. The evaluation device 20 can control the recording of the Raman
spectrum by the Raman spectroscopy system 10.
The evaluation device 20 comprises an interface 21 in order to
receive data from the image sensor 16 of the Raman spectroscopy
system 10. The evaluation device comprises an integrated
semi-conductor circuit 22 which can comprise a processor or
controller and which is configured to evaluate the recorded Raman
spectrum in order to determine [Translator--end of sentence is
missing]. The integrated semi-conductor circuit 22 is configured to
determine by means of the Raman spectrum whether the blood reserve
2 can still be used for a transfusion. The integrated
semi-conductor circuit 22 can be configured in particular in order
to determine by means of evaluating the Raman spectrum whether and
to what extent the functionality of the cells is impaired. The
integrated semi-conductor circuit 22 can be configured to determine
by means of evaluating the Raman spectrum whether a cell death of
erythrocytes and/or thrombocytes and/or granulocytes and/or
leukocytes has occurred. The integrated semi-conductor circuit 22
can be configured to determine by means of evaluating the Raman
spectrum whether biological molecules of the cells are present,
which impair the function of the cell.
As is described in detail with reference to FIG. 2 to FIG. 11, the
integrated semi-conductor circuit 22 can be configured to identify
the presence or absence of determined Raman peaks or to determine
the spectral weight of Raman peaks which relate to the quality of
the blood reserve 2. For example, the integrated semi-conductor
circuit 22 can identify and/or further evaluate Raman peaks, which
are assigned to red blood cells or which are assigned to a cell
death of erythrocytes and/or thrombocytes, granulocytes,
leukocytes. The integrated semi-conductor circuit 22 can be
configured to evaluate for example the Raman spectrum in at least
one predefined wavenumber range, e.g. the Raman spectrum in the
wavenumber range between 1296 cm.sup.-1 and 1333 cm.sup.-1 in order
to determine whether the blood-based product 3 can be used for a
transfusion.
The integrated semi-conductor circuit 22 can be configured to
automatically verify the sterility of the blood reserve 2 by
analysing the Raman spectrum. The integrated semi-conductor circuit
22 can be configured to identify one or a plurality of Raman peaks,
which are assigned to impurities, for example bacteria or viruses,
in order to determine whether the blood reserve 2 is sterile.
The evaluation device 20 can comprise a memory 23 in which
comparative data 24 is stored which the integrated semi-conductor
circuit 22 can use when evaluating the Raman spectrum.
Information regarding the position and/or the spectral weight of
different Raman peaks for the different cell types of one or a
plurality of blood-based products can be stored in a non-volatile
manner in the memory 23 of the device 1. Alternatively or
additionally, the information regarding the position and/or the
spectral weight of different Raman peaks for the different
blood-based products can be determined by the device 1 by means of
methods of supervised learning or other machine learning
techniques.
The evaluation device 20 can comprise an optical and/or acoustic
output unit 25, via which the information dependent on the analysis
of the Raman spectrum is output, which shows whether or not the
blood reserve 2 can still be used. The output unit 25 can also be
structurally integrated into a housing of the evaluation device 20
or of the Raman spectroscopy system 10.
Even though the evaluation device 20 and the Raman spectroscopy
system 10 in FIG. 1 are schematically illustrated as separate
units, the functions of the evaluation device 20 can also be
integrated into a housing of the Raman spectroscopy system 10. The
Raman spectroscopy system 10 and the evaluation device 20 can be
designed as mobile, in particular portable units.
FIG. 2 is a flow diagram of a method 30. The method 30 can be
performed fully automatically by the device 1 without intermediate
operational actions of a user or it can be performed dependent on
user inputs. A sample 9 can be obtained from the blood-based
product 9. For example, a quantity of the blood-based product 3 can
be removed from the blood reserve 2 using a syringe. The quantity
of the blood-based product 3 removed can be thinned in order to
produce the sample 9. More than one sample can also be produced and
analysed using Raman spectroscopy. For example, impurities can be
firstly concentrated from samples of blood-based product removed
from the blood reserve 2, for example by separating erythrocytes
and/or thrombocytes and producing conditions which lead to a
reproduction of any impurities present in the removed sample.
In this manner, the quantitative determination of impurities can be
improved for verifying the sterility. The sample 9 can also be
present in solid form. For example, the removed quantity of the
blood-based product 3 can be a droplet, which is firstly left to
evaporate in order to use the material remaining after evaporation
as the sample 9. The sample 9 can be a pellet.
In the case of step 31, the device 1 receives the sample 9. For
example, a sample holder 19 can be automatically drawn in after the
sample 9 has been placed there.
In the case of step 32, a Raman spectrum of the sample 9 is
recorded. The light source 11 is controlled such that an excitation
beam 17 is produced. The excitation beam 17 or a beam of
electromagnetic radiation different from the excitation beam 17 can
produce an optical trap in which cells of the sample 9 are
collected for Raman spectroscopy, for example if the sample 9 is
liquid.
A plurality of Raman spectra can also be recorded. For example, a
plurality of Raman spectra can be recorded for the same sample or
different samples in order to determine from a Raman spectrum
whether the erythrocytes and/or thrombocytes and/or leukocytes are
alive and in order to determine from a different Raman spectrum how
many impurities the blood reserve contains.
In the case of step 33, the evaluation device 20 evaluates the
recorded Raman spectrum. The evaluation device 20 can identify
Raman peaks, which are for example assigned to guanine,
deoxyribonucleic acid or to a cell death of erythrocytes or
thrombocytes. The evaluation device 20 can identify Raman peaks
which are assigned to red blood cells. The evaluation device 20 can
carry out a static evaluation of the Raman spectrum, for example by
means of a spectral analysis.
In the case of step 34, depending on the evaluation of the Raman
spectrum, it is verified whether the blood reserve 2 with the
blood-based product 3 may be used for a transfusion. To this end,
the evaluation device 20 can for example compare a spectral weight
of a Raman peak, which is assigned to the cell death of
erythrocytes or thrombocytes, with a threshold value. Depending on
whether the spectral weight of Raman peaks, which is associated
with the cell death of erythrocytes or thrombocytes, is greater
than the threshold value, it can be determined that the sample is
no longer suitable for the transfusion. Alternatively or
additionally, data points, which have been determined by a spectral
analysis of the Raman spectrum, can be used in order to determine
whether the blood reserve is already old or has been stored such
that it can no longer be used for a transfusion. Alternatively or
additionally, it can be determined by means of the analysis of the
Raman spectrum whether the sample is still sterile. A type and a
number of impurities can be estimated.
In the case of step 35 or step 36, an output unit is actuated such
that information is indicated, which shows whether or not the blood
reserve can still be used.
FIG. 3 schematically shows a Raman spectrum 40 which is evaluated
by the evaluation device 20. The Raman spectrum 40 can comprise a
plurality of Raman peaks 41, 42 which can be automatically
identified by the evaluation device 20 and which provide
information regarding whether the blood reserve can still be used.
The Raman peaks 41, 42 can for example be associated with
substances which indicate a cell death (e.g. apoptosis) of
erythrocytes or thrombocytes. The Raman peaks 41, 42 can be
assigned to red blood cells. For example, one or a plurality of the
analysed Raman peaks can be in wavenumbers which are selected from
the group consisting of 669 cm.sup.-1, 750 cm.sup.-1, 752
cm.sup.-1, 999 cm.sup.-1, 1122 cm.sup.-1, 1210 cm.sup.-1, 1444
cm.sup.-1, 1543 cm.sup.-1 and 1617 cm.sup.-1.
The evaluation device 20 can, in a targeted manner, analyse only a
predefined wavenumber range or a plurality of predefined wavenumber
ranges of the Raman spectrum 40 in order to determine whether the
blood reserve is still suitable for a transfusion. The evaluation
device 20 can for example analyse a wavenumber range of 1200
cm.sup.-1 to 1400 cm.sup.-1. The evaluation device 20 can for
example analyse a wavenumber range of 1276 cm.sup.-1 to 1333
cm.sup.-1. Other wavenumber ranges can be used, for example
wavenumber ranges in which there are characteristic Raman peaks of
red blood cells.
FIG. 4 schematically shows the Raman spectrum 40 which is evaluated
by the evaluation device 20. A wavenumber range of 1276 cm.sup.-1
to 1333 cm.sup.-1 is illustrated only as an example, in which there
are one or a plurality of Raman peaks 41, 42, which are identified
by the evaluation device 20. A further evaluation by a spectral
analysis can take place. For example, the evaluation device 20 can
determine an integral 44, 45 of the signal 40 for the respective
Raman peaks 41, 42, e.g. by numeric integration or totaling the
signal amounts in a plurality of discrete wavenumber bands in order
to obtain a measure for the spectral weight of the Raman peaks 41,
42. Further evaluations can be carried out, for example by a
principal component analysis of the Raman spectrum 40, by
evaluating the mean value spectrum or by a SVM, without being
limited thereto.
FIG. 5 and FIG. 6 illustrate exemplary results of a principal
component analysis or a different cluster analysis which is
performed by the evaluation device 20 in order to determine whether
the blood reserve is still suitable for a transfusion. In this
connection, the principal component analysis is performed for a
Raman spectrum or a plurality of Raman spectra which have been
recorded from the sample 9. The data points are illustrated
according to a pair of different principal components PC-1 and
PC-2. FIG. 5 shows the data points 51 which have been obtained by
processing the Raman spectrum of a relatively fresh blood reserve.
FIG. 6 shows data points 52 which have been obtained by processing
the Raman spectrum of a blood reserve which has been stored for
longer and/or not at the correct temperature.
As can be discerned from a comparison of FIG. 5 and FIG. 6, the
data points obtained by the principal component analysis are
shifted depending on whether or not the blood reserve is still
suitable for the transfusion. Accordingly, the evaluation device 20
can automatically determine by means of the principal component
analysis of a Raman spectrum whether the respectively tested blood
reserve 2 is still suitable for a transfusion.
Different regions 53, 54 can be defined in an N-dimensional space
in which the points of the cluster analysis are arranged depending
on whether cellular components of the blood-based product are
intact cells or functionally impaired cells.
The data points, assigned to fresh and thus intact cellular
components, can be arranged in a region 53. The data points,
assigned to old and functionally modified cellular components, can
be arranged in a region 54 of the N-dimensional space different
therefrom. The dimension N of the space in which the cluster
analysis is performed can be greater than two, in particular many
times greater than two.
In order to identify which proportion of cells of a cell type, e.g.
which proportion of erythrocytes, thrombocytes, granulocytes or
leukocytes is subject to a functional modification, which makes the
blood-based product unsuitable for a transfusion, the evaluation
device 20 can thus be configured to perform a cluster analysis of a
plurality of Raman spectra of cells of this cell type. The cluster
analysis can be a principal component analysis. The evaluation
device 20 can be configured to quantitatively identify by means of
the cluster analysis whether cells have to be assigned to a cluster
51 of intact cells or to a different cluster 52 of functionally
impaired cells. The number of cells in the different clusters 51,
52 can be determined by the evaluation device 20 in order to
determine which proportion of cells of the cell type is subject to
the functional modification.
For blood-based products, which comprise a plurality of different
cellular components of the blood, the evaluation device 20, by
means of a cluster analysis, can distinguish not only between
intact cells and functionally modified cells, but also between
different cell types. For each of the plurality of different cells
types, it can then be determined which proportion of cells of this
cell type is subject to a functional modification.
FIG. 7 and FIG. 8 show the results of a cluster analysis, e.g. of a
principal component analysis for a further cell type which is
different from the further cell types examined in FIG. 5 and FIG.
6. FIG. 7 and FIG. 8 show, by way of example, results for
erythrocytes in comparison with exemplary results for thrombocytes
like those illustrated in FIG. 5 and FIG. 6. FIG. 7 and FIG. 8 show
arrangements of data points, of which each is assigned to a Raman
spectrum in an N-dimensional data space in the case of a principal
component analysis. Other techniques of the cluster analysis can be
used. FIG. 7 shows, by way of example, data points for Raman
spectra of fresh intact cells. FIG. 8 shows, by way of example,
data points for Raman spectra of old, functionally modified cells.
As explained with reference to FIG. 5 and FIG. 6, by means of the
cluster analysis, a distinction can be made between data 56, which
can be assigned to intact cells, and data 57, which can be assigned
to functionally modified cells.
Data points, which belong to cells of different cell types, are
also in different regions of the data space in the case of the
cluster analysis. Different cells can thus be distinguished. An
assignment of data points to cellular components such as
erythrocytes, thrombocytes, granulocytes or leukocytes can take
place by a comparison with the position of data points assigned to
intact cells. Such reference data can be stored in a non-volatile
manner in the device 1.
As is illustrated by way of example in FIG. 7 in comparison to FIG.
5, the region 58, in which there are data points for cells of a
second cell type in the case of the cluster analysis, differs from
the region 53, in which there are data points for cells of a second
cell type in the case of the cluster analysis.
Functional modifications of the cells, e.g. due to age or storage
conditions of the blood-based product, lead to a shifting of the
data points in the case of the cluster analysis from the region 58
into a region 59 different therefrom.
The evaluation device 20 can carry out an assignment to different
cell types for example by means of different wavenumber ranges in
the case of a cluster analysis or in the case of a different
analysis of the recorded Raman spectra, in which wavenumber ranges
the Raman spectra for cells of different cell types respectively
comprise a characteristic behaviour. In order to identify
thrombocytes and/or in order to identify functional modifications
of thrombocytes, at least one wavenumber in the wavenumber range of
1296 cm.sup.-1 to 1333 cm.sup.-1 can for example be evaluated by
means of the evaluation device 20 in order to determine whether the
blood-based product can be used for a transfusion.
In order to identify erythrocytes and/or in order to identify
functional modifications of erythrocytes by means of the evaluating
device 20, at least one wavenumber from one or a plurality of
wavenumber regions from 1650 to 1600 cm.sup.-1, from 1350 to 1250
cm.sup.-1, from 1180 cm.sup.-1 to 1120 cm.sup.-1, from 1100
cm.sup.-1 to 1050 cm.sup.-1, from 930 cm.sup.-1 to 890 cm.sup.-1 or
from 700 cm.sup.-1 to 650 cm.sup.-1 can for example be evaluated in
order to determine whether the blood-based product can be used for
a transfusion.
Depending on the proportion of cells of one or a plurality of cell
types, which are subject to a functional modification, the
evaluation device 20 can automatically determine whether the
blood-based product is suitable for a transfusion.
A threshold value for a cell type of the blood-based product can be
stored in a non-volatile manner in the device 1. If the proportion
of cells of the cell type, which are functionally impaired after
the result of the principal component analysis or a different
cluster analysis, exceeds the threshold value, the evaluation
device 20 automatically identifies that the blood-based product is
not suitable for the transfusion.
A further threshold value for a further cell type of the
blood-based product can be stored in a non-volatile manner in the
device 1. If the proportion of cells of the further cell type,
which are functionally impaired after the result of the principal
component analysis or a different cluster analysis, exceeds the
further threshold value, the evaluation device 20 automatically
identifies that the blood-based product is not suitable for the
transfusion.
The cell type and the further cell type can both be selected from a
group consisting of erythrocytes, thrombocytes, granulocytes and
leukocytes.
FIG. 9 shows a Raman spectrum 71 of thrombocytes and a Raman
spectrum 72 of erythrocytes. Mean value spectra are respectively
illustrated according to storage of the blood-based product.
The position of Raman peaks enables a distinction of different cell
types. For example, the Raman spectrum 71 of thrombocytes comprises
Raman peaks in the case of a wavenumber or a plurality of
wavenumbers 74, which enable a distinction of thrombocytes and
other cell types. In a wavenumber range 84 or in a plurality of
wavenumber ranges, which can reach for example from 1550 cm.sup.-1
to 1590 cm.sup.-1, a cell of the cell type thrombocytes can be
identified from the presence of a Raman peak.
The Raman spectrum 72 of erythrocytes comprises Raman peaks in the
case of wavenumbers 75, 76, 77, which allow a distinction between
thrombocytes and other cell types. In a wavenumber range or in a
plurality of wavenumber ranges 85, 76, 87, a cell of the cell type
erythrocytes can be identified from the presence of a Raman peak.
The one or plurality of wavenumber ranges 85, 86, 87 can be
selected from the group consisting of a wavenumber range from 1480
cm.sup.-1 to 1550 cm.sup.-1, a wavenumber range from 1050 cm.sup.-1
to 1120 cm.sup.-1 and a wavenumber range from 600 cm.sup.-1 to 700
cm.sup.-1.
In order to distinguish different cell types and the functional
modifications, to which the cells are respectively subjected, a
cluster analysis can be performed, as has already been described
above.
In addition to a determination of the proportions of cellular
components of the blood-based products, which are subjected to
functional modifications, impurities such as contaminations,
bacteria or viruses can also be identified by the Raman
spectroscopy.
With devices and methods according to exemplary embodiments,
objective statements can be made regarding whether the blood
reserve 2 may be used for a transfusion. The quantitative
evaluation of the Raman spectrum provides objective information on
the cells present and/or regarding whether the function of a
significant proportion of erythrocytes or thrombocytes is impaired,
for example by cell death or other processes. The quantitative
evaluation of the Raman spectrum can, alternatively or
additionally, be used in order to identify impurities and thus to
verify the sterility of the blood reserve.
For the best possible evaluation even in the case of smaller sample
quantities, the device 1 can be configured such that cells for
example erythrocytes or thrombocytes are held in an optical trap in
the case of the Raman spectroscopy. The optical trap can be
produced by the excitation beam 17 of the Raman spectroscopy system
1 or a beam of electromagnetic radiation different therefrom.
FIG. 10 shows, by way of example, a configuration 60 in the case of
a device 1 according to an exemplary embodiment, in which
biological objects are held in an optical trap in order to perform
the Raman spectroscopy. A focal point 61 of a beam produces an
optical trap potential, in which biological objects 62-64 are
collected for the Raman spectroscopy. The focal point 61 can be
produced by the excitation beam 17, which is output by the light
source 11. The excitation beam 17 can thus be used both as
excitation for the Raman scattering and for producing the optical
trap. Alternatively, the optical trap can also be produced by a
separate beam.
The Raman spectroscopy system 10 can also comprise a light
conductor, for example an optical fibre, by means of which the
excitation beam 17 and/or the Raman scattered light is guided. The
light conductor can be positioned such that the excitation beam
leaving said light conductor produces the optical trap with the
focal point 61.
While exemplary embodiments have been described with reference to
the figures, variations can be implemented in the case of further
exemplary embodiments. For example, the Raman spectrum can be
evaluated in a number of different wavenumber ranges or with a
number of different methods of the spectral analysis in order to
determine whether the blood-based product may be used for a
transfusion. While exemplary embodiments have been described, in
the case of which the sample is produced by removing it from a
blood-based product, in the case of further exemplary embodiments
the Raman spectroscopy can be performed on the blood reserve
itself.
FIG. 11 shows a blood reserve 2 with a bag 5 made from plastic
material. For use in the case of methods or devices according to
exemplary embodiments, the bag 5 can consist of a material which
has high transmissivity for the excitation beam and the Raman
scattered light of the relevant biological objects.
The bag 5 can comprise a window 6 made of a material which has high
transmissivity for the excitation beam and the Raman scattered
light of the relevant biological objects (for example erythrocytes,
thrombocytes, bacteria and/or germs). The device 1 can comprise an
object slide which is configured to receive the bag 5 such that the
window 6 is positioned so as to allow the excitation beam from the
light source 11 to pass through and the Raman scattered light to
exit to the Raman spectrometer 14.
While devices and methods have been described in the context of
quality controlling blood-based products with reference to FIG. 1
to FIG. 11, Raman spectroscopy can also be used in order to
identify diseases or progressions of disease.
Accordingly, the device 1 from FIG. 1 can also be configured to
process a blood sample 9 of a patient. The device 1 can evaluate
the recorded Raman spectrum in order to identify a disease or a
progression of disease. The device 1 can record and evaluate Raman
spectra of a plurality of blood samples 9, which have been obtained
in a time-sequential manner, in order to identify a progression of
disease.
The device 1 can be configured to identify and evaluate, for
example Raman peaks which are assigned to erythrocytes or
thrombocytes. The device 1 can be configured to identify and
evaluate, for example Raman peaks which are assigned to
leukocytes.
By means of evaluating the recorded Raman spectrum or the recorded
Raman spectra, an illness in the patient, from whom the blood
sample 9 has been taken, can be identified. The evaluation can take
place automatically by means of the device 1.
The device 1 can for example be configured to identify a disease or
a progression of a disease which is selected from a group
consisting of tumour diseases, blood coagulation disorders (e.g.
PMH) or thrombosis. The device 1 can be configured to perform a
spectral analysis of the recorded Raman spectrum or the recorded
Raman spectra in order to identify the disease or the progression
of disease.
Devices and methods according to exemplary embodiments can
generally be used for quantitatively examining blood, for example
for quality controlling blood reserves in blood banks.
* * * * *
References